8 research outputs found
Antibodies as Carrier Molecules: Encapsulating Anti-Inflammatory Drugs inside Herceptine
The
human epidermal growth factor receptor 2 (HER2) is overexpressed
in about a third of breast cancer patients, with a strong involvement
of the cyclooxygenase-2 (COX-2) enzyme in the tumor progress. HER2
and COX-2 are consequently potential targets for inhibiting carcionogenesis.
Herceptin (trastuzumab) is an antibody that partially blocks HER2-positive
cancers at their initial stage. Unfortunately, the overall response
rate to the single treatment with this antibody is still modest, and
therefore, it needs to be improved by combining several chemotherapeutic
agents. On the other hand, nonsteroidal anti-inflammatory drugs (NSAIDs)
are designed to halt COX-2 functionality, so they might also exhort
an anticancer activity. In this contribution, dual HerceptināNSAID
drugs are designed using theoretical tools. More specifically, blind
docking, molecular dynamics, and quantum calculations are performed
to assess the stability of 14 NSAIDs embedded inside Herceptin. Our
calculations reveal the feasibility of improving the antitumor activity
of the parent Herceptin by designing a dual HER2-targeting with Etofenamate.
That coupling mode might be used to further rationalize new clinical
strategies beyond classical antibody dosages
Erratum: Harmonic Models in Cartesian and Internal Coordinates to Simulate the Absorption Spectra of Carotenoids at Finite Temperatures
Erratum:
Harmonic Models in Cartesian and Internal
Coordinates to Simulate the Absorption Spectra of Carotenoids at Finite
Temperature
Harmonic Models in Cartesian and Internal Coordinates to Simulate the Absorption Spectra of Carotenoids at Finite Temperatures
When large structural
displacements take place between the ground state (GS) and excited
state (ES) minima of polyatomic molecules, the choice of a proper
set of coordinates can be crucial for a reliable simulation of the
vibrationally resolved absorption spectrum. In this work, we study
two carotenoids that undergo structural displacements from GS to ES
minima of different magnitude, from small displacements for violaxanthin
to rather large ones for Ī²-carotene isomers. Their finite-temperature
(77 and 300 K) spectra are simulated at the harmonic level, including
Duschinsky effect, by time-dependent (TD) and time-independent (TI)
approaches, using (TD)ĀDFT computed potential energy surfaces (PES).
We adopted two approaches to construct the harmonic PES, the Adiabatic
(AH) and Vertical Hessian (VH) models and, for AH, two reference coordinate
frames: Cartesian and valence internal coordinates. Our results show
that when large displacements take place, Cartesian coordinates dramatically
fail to describe curvilinear displacements and to account for the
Duschinsky matrix, preventing a realistic simulation of the spectra
within the AH model, where the GS and ES PESs are quadratically expanded
around their own equilibrium geometry. In contrast, internal coordinates
largely amend such deficiencies and deliver reasonable spectral widths.
As expected, both coordinate frames give similar results when small
displacements occur. The good agreement between VH and experimental
line shapes indicates that VH model, in which GS and ES normal modes
are both evaluated at the GS equilibrium geometry, is a good alternative
to deal with systems exhibiting large displacements. The use of this
model can be, however, problematic when imaginary frequencies arise.
The extent of the nonorthogonality of the Dushinsky matrix in internal
coordinates and its correlation with the magnitude of the displacement
of the GS and ES geometries is analyzed in detail
Conformational Changes of Trialanine in Water Induced by Vibrational Relaxation of the Amide I Mode
Most of the protein-based diseases
are caused by anomalies in the
functionality and stability of these molecules. Experimental and theoretical
studies of the conformational dynamics of proteins are becoming in
this respect essential to understand the origin of these anomalies.
However, a description of the conformational dynamics of proteins
based on mechano-energetic principles still remains elusive because
of the intrinsic high flexibility of the peptide chains, the participation
of weak noncovalent interactions, and the role of the ubiquitous water
solvent. In this work, the conformational dynamics of trialanine dissolved
in water (D<sub>2</sub>O) is investigated through Molecular Dynamics
(MD) simulations combined with instantaneous normal modes (INMs) analysis
both at equilibrium and after the vibrational excitation of the C-terminal
amide I mode. The conformational equilibrium between Ī± and pPII
conformers is found to be altered by the intramolecular relaxation
of the amide I mode as a consequence of the different relaxation pathways
of each conformer which modify the amount of vibrational energy stored
in the torsional motions of the tripeptide, so the Ī± ā
pPII and pPII ā Ī± conversion rates are increased differently.
The selectivity of the process comes from the shifts of the vibrational
frequencies with the conformational changes that modify the resonance
conditions driving the intramolecular energy flows
Structure, Spectra, and DFT Simulation of Nickel Benzazolate Complexes with Tris(2-aminoethyl)amine Ligand
Benzazolate complexes of NiĀ(II),
[NiĀ(pbz)Ā(tren)]ĀClO<sub>4</sub> (pbz = 2-(2ā²-hydroxyphenyl)-benzimidazole
(pbm), <b>1</b>, 2-(2ā²-hydroxyphenyl)-benzoxazole (pbx), <b>2</b>, 2-(2ā²-hydroxyphenyl)-benzothiazole (pbt), <b>3</b>; tren = trisĀ(2-aminoethyl)Āamine), are prepared by self-assembly
reaction and structurally characterized. Theoretical DFT simulations
are carried out to reproduce the features of their crystal structures
and their spectroscopic and photophysic properties. The three complexes
are moderately luminescent at room temperature both in acetonitrile
solution and in the solid state. The simulations indicate that the
absorption spectrum is dominated by two well-defined transitions,
and the electronic density concentrates in three MOs around the benzazole
ligands. The Stokes shifts of the emission spectra of complexes <b>1</b>ā<b>3</b> are determined by optimizing the electronic
excited state
DFT Simulation of Structural and Optical Properties of 9āAminoacridine Half-Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA
In this work, we
use DFT-based methods to simulate the chemical
structures, optical properties, and interaction with DNA of a recently
synthesized chelated C^N 9-aminoacridine arene RuĀ(II) anticancer agent
and two new closely related RhĀ(III) and IrĀ(III) complexes using DFT-based
methods. Four chemical models and a number of theoretical approaches,
which representatively include the PBE0, B97D, ĻB97X, ĻB97X-D,
M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and
def2-TZVP basis sets, are tested. The best overall accuracy/cost performance
for the optimization process is reached at the ĻB97X-D/def2-SVP
and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules
(CHCl<sub>3</sub>) further refines the geometry, while taking into
account the crystal network gives no significant improvements of the
computed bond distances and angles. The analysis of the excited states
reveals that the M06 level matches better the experimental absorption
spectra, compared to ĻB97X-D. The use of the M06/def2-SVP approach
is therefore a well-balanced method to study theoretically the bioactivity
of this type of antitumoral complexes, so we couple this TD-DFT approach
to molecular dynamics simulations in order to assess their reactivity
with DNA. The reported results demonstrate that these drugs could
be used to inject electrons into DNA, which might broaden their applications
in photoactivated chemotherapy and as new materials for DNA-based
electrochemical nanodevices
DFT Simulation of Structural and Optical Properties of 9āAminoacridine Half-Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA
In this work, we
use DFT-based methods to simulate the chemical
structures, optical properties, and interaction with DNA of a recently
synthesized chelated C^N 9-aminoacridine arene RuĀ(II) anticancer agent
and two new closely related RhĀ(III) and IrĀ(III) complexes using DFT-based
methods. Four chemical models and a number of theoretical approaches,
which representatively include the PBE0, B97D, ĻB97X, ĻB97X-D,
M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and
def2-TZVP basis sets, are tested. The best overall accuracy/cost performance
for the optimization process is reached at the ĻB97X-D/def2-SVP
and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules
(CHCl<sub>3</sub>) further refines the geometry, while taking into
account the crystal network gives no significant improvements of the
computed bond distances and angles. The analysis of the excited states
reveals that the M06 level matches better the experimental absorption
spectra, compared to ĻB97X-D. The use of the M06/def2-SVP approach
is therefore a well-balanced method to study theoretically the bioactivity
of this type of antitumoral complexes, so we couple this TD-DFT approach
to molecular dynamics simulations in order to assess their reactivity
with DNA. The reported results demonstrate that these drugs could
be used to inject electrons into DNA, which might broaden their applications
in photoactivated chemotherapy and as new materials for DNA-based
electrochemical nanodevices
Structure and Spectroscopic Properties of Nickel Benzazolate Complexes with Hydrotris(pyrazolyl)borate Ligand
The reaction of benzazole
ligands 2-(2ā²-hydroxylphenyl)Ābenzimidazole (Hpbm), 2-(2ā²-hydroxylphenyl)Ābenzoxazole
(Hpbx), and 2-(2ā²-hydroxylphenyl)Ābenzothiazole (Hpbt),
with [NiĀ(Tp*)Ā(Ī¼-OH)]<sub>2</sub> (Tp* = hydrotrisĀ(3,5-dimethylpyrazolyl)Āborate),
leads to pentacoordinate nickel complexes [NiĀ(Tp*)Ā(pbz)] (pbz
= pbm (<b>1</b>), pbx (<b>2</b>), pbt (<b>3</b>)).
The structures of <b>1</b>, <b>2</b>, and <b>3</b> were determined by X-ray crystallography. The pentacoordinate nickel
complexes have distorted trigonal bipyramidal geometries with Addisonās
Ļ parameter values of 0.63, 0.73, and 0.61 for <b>1</b>, <b>2</b> and <b>3</b>, respectively. The benzazolates
are bonded in an Ī·<sup>2</sup>(N,O) fashion to the nickel atoms.
DFT calculations are carried out to optimize the structures of the
three complexes giving a good agreement with the X-ray structures.
The <sup>1</sup>H NMR spectra of complexes <b>1</b>ā<b>3</b> exhibit sharp isotropically shifted signals. The complete
assignment of these signals required an application of two-dimensional
{<sup>1</sup>Hā<sup>1</sup>H}-COSY techniques. The experimental
absorption spectra of the three complexes in chloroform solution each
show an intense absorption band in the ultraviolet region ca. 240
nm, followed by three less intense bands, the first two at ā¼295
and ā¼340 nm, and the last more disperse one, at wavelengths
between 360 and 410 nm. The absorption spectra are simulated by TD-DFT
and reproduce the main features of the experimental spectra well.
The analysis of the electronic transitions by inspection of the frontier
molecular orbitals and also the natural transition orbitals allowed
us to characterize and assign the observed bands properly. The three
complexes are moderately blue luminescent at room temperature, both
in the solid state and in solution. Emission spectra at room temperature
display broad structureless bands in chloroform solution at 460, 482,
and 512 nm for complexes <b>1</b>, <b>2</b> and <b>3</b>, respectively, and structured emission in solid state with
Ī»<sub>max</sub> values of 473, 486, and 516 nm. Complexes containing
different donor atoms in the benzazole ligand are furthermore observed
to give different luminescence responses in the presence of ZnĀ(II),
CdĀ(II), HgĀ(II), and CuĀ(II)